Project 1: Pancreatic cancer is one of the most aggressive adult solid tumors and patient survival at diagnosis is measured in months. Pancreatic tumors have a poorly developed blood supply leading to low oxygen levels while their rapid growth causes them to outstrip their blood supply further aggravating the lack of oxygen. Hypoxia is extremely hostile environment for normal cell growth but pancreatic cancer cells have adapted to thrive in low oxygen through the increased expression of the hypoxia inducible transcription factor-1 (HIF-1). Genes induced by HIF-1 allow pancreatic cancer cells to survive hypoxia by changing to an anaerobic energy metabolism, to become resistant to programmed cell death (apoptosis), to produce cytokines that promote the formation of new tumor capillary blood vessels (angiogenesis) and to metastasize. HIF-1 is a heterodimer of a hypoxia-inducible HIF-la subunit and a constitutive HIF-113 subunit. In air, HIF-la undergoes rapid ubiquitination and proteasomal degradation but in hypoxia the degradation is inhibited and HIF-la levels increase. Some pancreatic cancers show constitutive elevation of HIF-la even in air. We present evidence that a mechanism for the increase in HIF-la is through an increase in the levels of the redox proteins that are frequently elevated in pancreatic cancer. While hypoxia and increases in HIF- la makes pancreatic cancers very aggressive it also provides an achilles heel for treating the disease. Thus, the hypothesis upon which the work is based is that the redox regulation of HIF-la leading to increased levels of HIF-la in pancreatic cancer is responsible for their aggressive growth and resistance to therapy, and that drugs that block the redox regulation of HIF-la will have antitumor activity against pancreatic cancer. We have identified a novel small molecule inhibitor of HIF-1 a that shows remarkable antitumor activity against even large human pancreatic tumor xenografts in mice. We will perform definitive experimental and translational studies to identify the mechanism by which the drug inhibits HIF- 1ct in pancreatic cancer and conduct clinical trial in patients with pancreatic cancer. The long term objective is to understand the redox control of pancreatic cancer growth and to develop novel and effective treatments for the disease.